Heart disease and cardiac disorders are a major cause of death in the developed world. One particular category is described as acute cardiac disorders (ACD). ACDs are caused by the rupture or erosion of atheromatous plaques in epicardial coronary arteries. The exposure of the plaque core activates the clotting cascade and results in thrombosis within the plaque. This then initiates platelet aggregation. There are three possible mechanisms by which damage to the myocardium may then occur.
Firstly, intraluminal platelet aggregation may cause sufficient vascular occlusion for cardiomyocyte damage to occur. Occlusion does not have to be total to produce myonecrosis. Partial occlusion will produce a reduction in the rate of blood supply in the myocardium downstream. If there is already supply/demand mismatch in this area, the reduction in blood supply may be enough to render an area of myocardium non-viable. The tissue will then become sufficiently ischaemic for necrosis to occur. This is most likely to affect small areas of myocardium at the watersheds of different branches of the vascular supply.
The second mechanism is the release of platelet microaggregates. These will embolise small vessels causing ischaemia and localised infarction (Davies et al, 1986; Falk E, 1995).
Finally, progression of white thrombus formation to activation of the clotting cascade will result in partial or total occlusion of the vessel. Partial occlusion will produce ischaemia and necrosis if it produces inadequate flow to maintain tissue viability downstream, as described above. Total occlusion will initially produce ischaemia. This will progress to necrosis if maintained and there is inadequate or no collateral blood supply.
In order to either limit or prevent myocardial damage it is therefore desirable to detect ischaemia caused by cardiac disorders before it progresses to necrosis/infarction. In theory, if ischemia can be detected prior to progression to necrosis, it may be possible to intervene to either limit or prevent myocardial damage.
Attempts have been made to detect ischemia using a number of biomarkers, for example choline, unbound free fatty acids (FFAu) and ischemia-modified albumin (IMA®). Unfortunately all of these markers suffer from the disadvantage that assays relying on them can not easily discriminate between patients with or without cardiac disorders. In addition, although these assays may be sensitive, allowing early detection, they lack specificity. Furthermore, the markers are often chemically derived and are produced in any ischemia or as part of normal physiology, for example lactate or free fatty acids. Other early markers such as myoglobin and CK-MB isoenzyme are elevated in non-cardiac diseases such as skeletal muscle trauma/diseases and renal failure.
In light of the problems associated with ischemia biomarkers, tests for biomarkers of myocardial necrosis are used to diagnose cardiac disorders. The measurement of the cardiac troponins, cardiac troponin T (cTnT) and cardiac troponin I (cTnI), have become recognised as the diagnostic reference standard for myocardial necrosis and as such may be predictive for myocardial infarction. Release kinetics show troponin elevation occurs approximately 4-6 hours after the onset of the myocardial necrosis and peak at 12-14 hours. There is therefore a window of 4-6 hours in which myocardial damage is occurring, but a diagnosis cannot be made and the correct treatment cannot be initiated.
In addition, the sensitive nature of these tests has also revealed that myocardial necrosis is also found in a range of other clinical situations, highlighting the need to use all clinical information for diagnosis of cardiac disorders.
There is therefore a need in the art for methods which are capable of sensitively, specifically and rapidly detecting the onset of cardiac ischemia and myocardial necrosis caused by cardiac disorders at the earliest possible point.